373 – Thyroid function & hypothyroidism: how new approaches are transforming care

KEYPOINTS

• 01

  The thyroid mostly secretes inactive T4; tissues activate it into T3 as needed, and the whole system evolved to conserve iodine.

  Dr. Antonio Bianco, a thyroid physician-scientist who researches how T3 shapes chromatin and gene expression, explains that receptors bind T3 strongly and T4 barely. T4 has a half-life of about 8 days and T3 about 12 hours, so activation is brief and tightly controlled. Removing an iodine from T4's outer ring makes T3; removing one from the inner ring makes reverse T3, which is inactive and can't be converted back. Iodine is recycled each step.

• 02

  Three deiodinase enzymes decide how much T3 each tissue gets.

  D2 has about 1,000 times more affinity for T4 than D1 and makes roughly 80% of the T3 produced outside the thyroid. D1, in the liver and kidney, makes about 20%, clears reverse T3, and rises with insulin and carbohydrate intake. D3 only inactivates, turning T3 into T2 and T4 into reverse T3. Blood levels barely move (about 10–15%), while tissue T3 can swing tenfold within hours. Most T3 in the brain is made locally by D2.

• 03

  Fasting deliberately slows the thyroid: low insulin and leptin tell the hypothalamus to ease off.

  Peter's numbers from 7–10 day quarterly fasts: TSH rose from 2 to 7, free T3 fell from 0.3 to 0.2, and reverse T3 rose from 10 to 35. Bianco explains that TSH stays 'inappropriately normal' because the hypothalamus wants to save energy, and that T4 is shunted toward reverse T3 while low D1 activity slows its clearance. Weight loss plateaus partly for this reason. The free T3/reverse T3 ratio is a decent stand-in for deiodinase activity, which can't be measured from blood.

• 04

  TSH itself causes no symptoms, and the hypothalamic control center sits outside the blood-brain barrier.

  The chain runs TRH → TSH → T4. Symptoms come from too much or too little thyroid hormone, never from TSH itself. The mediobasal hypothalamus and pituitary are rich in D2 and read both blood T3 and locally converted T4. Diagnosis depends on TSH plus free T4. Free hormone matters because about 99.5% is bound to proteins like TBG; total T4 can read 14–15 in pregnancy while free T4 is normal.

• 05

  T3 and reverse T3 immunoassays are unreliable, especially at low levels, and mass spectrometry is needed.

  The free T4 immunoassay is good, but T3 assays track mass spec only at high values and diverge below about 90–100 ng/dL. When Bianco's lab ran one sample through four reverse T3 assays, the results were 'completely crazy'. He knows of no mainstream lab offering mass spec T3, and stick to the same lab for consistency.

• 06

  Hypothyroidism affects about 20 million Americans (4–5% of adults), mostly women at about 10 to 1, and is usually autoimmune.

  About 60% have TPO antibodies (Hashimoto's). Diagnosis typically needs a TSH above 10 with low free T4; a positive TPO with TSH around 4 and normal free T4 is the 'honeymoon' phase, monitored and repeated in about 3 months. Selenium, vitamin D or antioxidants may lower TPO and prolong the honeymoon, but that isn't standard care. TPO positivity alone in pregnancy raises the risk of miscarriage and prematurity.

• 07

  Graves' disease and hot nodules cause most hyperthyroidism, and the field is moving away from radioactive iodine.

  In Graves' an antibody mimics TSH: palpitations, tremor, weight loss, warm sweaty hands, TSH near zero. The options are antithyroid drugs for 1–3 years (30–40% remission), surgery by a high-volume surgeon (100–150 thyroidectomies a year), or radioactive iodine, now linked to more cancers. Hot nodules don't remit, so Bianco leans toward surgery.

• 08

  Levothyroxine fixes TSH but may leave tissues like the liver hypothyroid.

  T4 alone works for most patients, but in treated rats with normal TSH the liver stayed hypothyroid. Statins are the most common drug co-prescribed with levothyroxine, a hint that LDL clearance isn't fully restored. Bianco now treats hypothyroidism as a cardiometabolic risk factor requiring closer follow-up.

• 09

  For patients still symptomatic on T4, add T3, after ruling out look-alike conditions.

  Symptoms aren't specific: in blinded studies they can't separate hypothyroid from euthyroid people. Menopause is the biggest confounder (he orders FSH with TSH), along with anemia, iron deficiency and obesity. A low morning temperature doesn't mean low thyroid. Secondary (central) hypothyroidism is under 1% of cases and requires a low free T4. A healthy thyroid makes about 80% T4 and 20% T3; desiccated pig thyroid has been standardized since 1985, carries about a 4:1 ratio, and is as safe as T4 alone.